Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002042388 | SCV002291018 | likely pathogenic | not provided | 2022-09-26 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with clinical features of Hermansky-Pudlak syndrome (PMID: 16185271, 25400188, 27593200, 31141302, 32725903). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects HPS1 function (PMID: 16185271). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HPS1 protein function. ClinVar contains an entry for this variant (Variation ID: 1499624). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 668 of the HPS1 protein (p.Leu668Pro). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004526896 | SCV005039154 | pathogenic | Hermansky-Pudlak syndrome | 2024-03-25 | criteria provided, single submitter | clinical testing | Variant summary: HPS1 c.2003T>C (p.Leu668Pro) results in a non-conservative amino acid change located in the FUZ/MON1/HPS1, third Longin domain (IPR043970) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248842 control chromosomes (gnomAD). c.2003T>C has been reported in the literature in multiple individuals affected with Hermansky-Pudlak Syndrome (e.g. Ito_2005, Kanazu_2014, Wei_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant results in instability of the protein (Ito_2005). The following publications have been ascertained in the context of this evaluation (PMID: 16185271, 25400188, 27593200). ClinVar contains an entry for this variant (Variation ID: 1499624). Based on the evidence outlined above, the variant was classified as pathogenic. |